Treating cancer can be difficult in part because tumor cells can hijack normal cellular processes to resist treatment. For example, tumor cells can survive DNA damage that is induced by chemotherapeutic treatments by using normal cellular DNA repair pathways. Inhibitors of specific DNA repair pathways have been suggested as potential cancer treatments that could be used in combination with DNA-damaging chemotherapeutic therapies (Helleday, T., et al., Nature Reviews Cancer, 8, 193-204 (2008)). Unfortunately, the mechanisms underlying DNA repair pathways have not been fully elucidated.
The detection and repair of damaged DNA takes place in the context of chromatin. A variety of histone modifications including phosphorylation, acetylation, sumolation, and ubiquitylation are involved in the signaling events that trigger and transduce the DNA damage response (DDR) (T. Misteli, et al., Nat. Rev. Mol. Cell Biol., 10:243 (2009; H. van Attikum, et al., Trends Cell Biol., 19:207 (2009); J. W. Harper, et al., Mol. Cell, 28:739 (2007)). The DDR blocks cell cycle progression, recruits factors involved in DNA repair, and optionally triggers programs that control senescence or programmed cell death (S. P. Jackson, et al., Nature, 461:1071 (2009)). Although alterations in chromatin structure are known to be important for the initiation and propagation of the DNA damage response, the molecular details of these alterations are unclear. For example, histone acetylation is known to regulate chromatin dynamics (K. K. Lee, et al., Nat. Rev. Mol. Cell Biol., 8:284 (2007); R. Margueron, et al., Nat. Rev. Genet., 11:285 (2010)), but the mechanistic role of histone acetylation in the DDR is poorly understood (H. van Attikum, et al., Trends Cell Biol., 19:207 (2009); C. Das, et al., Nature, 459:113 (2009); J. Tjeertes, et al., EMBO J., 12 (2009)).
Therefore, it is an objection of the invention to provide compositions and methods for treating cancer by modulating the DDR in target cells, preferably cancer or precancerous cells.
It is also an object of the invention to provide compositions and methods for sensitizing tumor cells to DNA damaging agents such as ionizing radiation.
It is also an object of the invention to provide compositions and methods for protecting healthy cells from DNA damaging agents.
It is a further object of the invention to provide methods of determining whether cells will be sensitive to DNA damaging agents.
It is another object of the invention to provide methods for identifying agents that interfere with the DRR in specific cells or tissues.